We and our collaborators have demonstrated that 11- or 16-base oligonucleotides complementary to the 3'overhang sequence of the telomere (T-oligos) induce transient cell cycle arrest in normal human cells of most lineages, but cause apoptosis in human pancreatic cancer cells, as well as human lymphoma, melanoma, and prostate carcinomas. In preliminary data, we show that the T-oligos enhance the activity of taxanes on pancreatic carcinoma cells. In in vivo studies, we have also demonstrated that 11- or 16-mer T-oligos given IV, SC or IP generate dramatic systemic anti-tumor responses, without toxicity, in human xenograft models, and in a spontaneous murine model of aggressive human lymphoma. We hypothesize that these T-oligos may offer a new approach to treatment of pancreatic malignancies. We have demonstrated dramatic targeted cytotoxicity by the new 16-mer T-oligos towards multiple malignant human pancreatic cancer cell lines, representative of advanced pancreatic malignancies, in our preliminary studies. The same oligos had no effects on normal human epithelial cells in culture. We propose to: 1) demonstrate and optimize the cytotoxic / cytopathic effects of T-oligos on pancreatic cancer cells;2) elucidate the molecular mechanisms of cytotoxicity and the ability of the T-oligos to synergize with chemotherapy;and 3) test the anti-tumor activity and safety of T-oligos in vivo on human pancreatic cancer xenograft tumor models. The studies proposed here will provide a solid preclinical basis for the clinical development of this approach for the treatment of pancreatic cancer. PUBLIC HEALTH RELEVANCE: Current treatments for advanced pancreatic cancer are relatively ineffective and also relatively non-specific, in that they damage normal tissues as well as malignant tissues, leading to the side-effects and toxicities associated with radiation therapy and chemotherapy. We have developed a new targeted approach to the treatment of pancreatic cancer using a small DNA molecule, and have shown in preliminary studies that this agent is non-toxic to animals and produces a strong anti-cancer effect, and enhances the activity of the chemotherapeutic agents used in pancreatic cancer. We propose studies that will provide a solid preclinical basis for the subsequent clinical development of this novel therapeutic.